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      NAD + metabolism: pathophysiologic mechanisms and therapeutic potential

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          Abstract

          Nicotinamide adenine dinucleotide (NAD +) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation and xenobiotics. These effects are mainly achieved by the driving effect of NAD + on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Besides, multiple NAD +-dependent enzymes are involved in physiology either by post-synthesis chemical modification of DNA, RNA and proteins, or releasing second messenger cyclic ADP-ribose (cADPR) and NAADP +. Prolonged disequilibrium of NAD + metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder. In this review, we summarize recent advances in our understanding of the molecular mechanisms of NAD +-regulated physiological responses to stresses, the contribution of NAD + deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention.

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          TLR signaling augments macrophage bactericidal activity through mitochondrial ROS

          Reactive oxygen species (ROS) are essential components of the innate immune response against intracellular bacteria, and it is thought that professional phagocytes generate ROS primarily via the phagosomal NADPH oxidase (Phox) machinery 1 . However, recent studies have suggested that mitochondrial ROS (mROS) also contribute to macrophage bactericidal activity, although the mechanisms linking innate immune signaling to mitochondria for mROS generation remain unclear 2-4 . Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of the TLR signaling adapter tumor necrosis factor receptor-associated factor 6 (TRAF6) to mitochondria where it engages evolutionarily conserved signaling intermediate in Toll pathways (ECSIT), a protein implicated in mitochondrial respiratory chain assembly 5 . Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation. ECSIT and TRAF6 depleted macrophages exhibit decreased levels of TLR-induced ROS and are significantly impaired in their ability to kill intracellular bacteria. Additionally, reducing macrophage mROS by expressing catalase in mitochondria results in defective bacterial killing, confirming the role of mROS in bactericidal activity. These results therefore reveal a novel pathway linking innate immune signaling to mitochondria, implicate mROS as important components of antibacterial responses, and further establish mitochondria as hubs for innate immune signaling.
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            Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock.

            Mice deficient in the circadian transcription factor BMAL1 (brain and muscle ARNT-like protein) have impaired circadian behavior and demonstrate loss of rhythmicity in the expression of target genes. Here we report that Bmal1(-/-) mice have reduced lifespans and display various symptoms of premature aging including sarcopenia, cataracts, less subcutaneous fat, organ shrinkage, and others. The early aging phenotype correlates with increased levels of reactive oxygen species in some tissues of the Bmal1(-/- )animals. These findings, together with data on CLOCK/BMAL1-dependent control of stress responses, may provide a mechanistic explanation for the early onset of age-related pathologies in the absence of BMAL1.
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              CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism.

              Nicotinamide adenine dinucleotide (NAD) levels decrease during aging and are involved in age-related metabolic decline. To date, the mechanism responsible for the age-related reduction in NAD has not been elucidated. Here we demonstrate that expression and activity of the NADase CD38 increase with aging and that CD38 is required for the age-related NAD decline and mitochondrial dysfunction via a pathway mediated at least in part by regulation of SIRT3 activity. We also identified CD38 as the main enzyme involved in the degradation of the NAD precursor nicotinamide mononucleotide (NMN) in vivo, indicating that CD38 has a key role in the modulation of NAD-replacement therapy for aging and metabolic diseases.
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                Author and article information

                Contributors
                changlongli@scu.edu.cn
                shenguobo@126.com
                zoubingwen81@163.com
                Journal
                Signal Transduct Target Ther
                Signal Transduct Target Ther
                Signal Transduction and Targeted Therapy
                Nature Publishing Group UK (London )
                2095-9907
                2059-3635
                7 October 2020
                7 October 2020
                2020
                : 5
                : 227
                Affiliations
                [1 ]GRID grid.13291.38, ISNI 0000 0001 0807 1581, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, , Sichuan University, and Collaborative Innovation Center for Biotherapy, ; Chengdu, 610041 China
                [2 ]GRID grid.412901.f, ISNI 0000 0004 1770 1022, State Key Laboratory of Biotherapy and Cancer Center, , West China Hospital, and Collaborative Innovation Center for Biotherapy, ; Chengdu, 610041 China
                [3 ]GRID grid.411304.3, ISNI 0000 0001 0376 205X, School of Basic Medical Sciences, , Chengdu University of Traditional Chinese Medicine, ; Chengdu, Sichuan 611137 China
                [4 ]GRID grid.5253.1, ISNI 0000 0001 0328 4908, CCU Molecular and Radiation Oncology, German Cancer Research Center; Department of Radiation Oncology, , Heidelberg University Hospital, ; Heidelberg, Germany
                [5 ]GRID grid.7700.0, ISNI 0000 0001 2190 4373, First Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, , Theodor-Kutzer-Ufer 1-3, ; 68167 Mannheim, Germany
                [6 ]GRID grid.412901.f, ISNI 0000 0004 1770 1022, West China School of Basic Medical Sciences & Forensic Medicine, , West China Hospital, Sichuan University, ; Chengdu, 610041 China
                [7 ]GRID grid.412901.f, ISNI 0000 0004 1770 1022, Department of Thoracic Oncology and Department of Radiation Oncology, Cancer Center, , West China Hospital, Sichuan University, ; Chengdu, 610041 China
                Author information
                http://orcid.org/0000-0003-2247-7750
                http://orcid.org/0000-0002-0825-3657
                Article
                311
                10.1038/s41392-020-00311-7
                7539288
                33028824
                7bbcaadc-8a28-47d0-9a62-22b462d47557
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 22 May 2020
                : 4 August 2020
                : 20 August 2020
                Categories
                Review Article
                Custom metadata
                © The Author(s) 2020

                diseases,molecular biology
                diseases, molecular biology

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